scholarly journals BET Protein Inhibition Evidently Enhances Sensitivity to PI3K/mTOR Dual Inhibition in Intrahepatic Cholangiocarcinoma

2021 ◽  
Author(s):  
Xiaolong Miao ◽  
Weihua Gong
Keyword(s):  
Targeted Therapy ◽  
Combination Therapy ◽  
Intrahepatic Cholangiocarcinoma ◽  
Molecular Targeted Therapy ◽  
Primary Liver Cancer ◽  
Mtor Inhibitors ◽  
Dual Inhibitor ◽  
Hydrodynamic Transfection

Abstract Background & Aims: Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis. Molecular targeted therapy is a promising treatment strategy. However, resistance to molecular-targeted therapy is inevitable and represents a major clinical challenge. Our objective was to provide a novel and efficient therapeutic strategy in treating primary ICC.Approach & Results: We generated an orthotopic ICC mouse model through hydrodynamic transfection of AKT and YAP into mouse liver. Genetic approaches were applied to study the mechanism that mediated resistance to a PI3K/mTOR dual inhibitor in mediating AKT/YapS127A-driven tumorigenesis. Haematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied to assess the efficacy of ICC combination therapy in vitro and in vivo.Conclusions: We confirmed that mTOR signalling is the most significantly affected pathway in ICC. BEZ235, a novel PI3K/mTOR dual inhibitor, can suppress the proliferation, invasion and colony formation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. The inhibition of PI3K/mTOR allowed the upregulation of c-Myc and YAP through the suppression of the phosphorylation of LATS1. This is a novel mechanism that mediates resistance to PI3K/mTOR dual inhibitors. However, BET inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment of ICC in vitro and in vivo. Our data further confirmed that the combination of a PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1a.

scholarly journals BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Xiaolong Miao ◽  
Chen Liu ◽  
Yuancong Jiang ◽  
Yao Wang ◽  
Deqiang Kong ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Intrahepatic Cholangiocarcinoma ◽  
Molecular Targeted Therapy ◽  
Antitumour Activity ◽  
Primary Liver Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Dual Inhibitor

AbstractIntrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.

scholarly journals SPDR-1 HSP90 inhibition overcomes resistant to molecular targeted therapy in BRAFV600E mutant glioblastoma

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi3-vi3
Author(s):  
Jo Sasame ◽  
Naoki Ikegaya ◽  
Yohei Miyake ◽  
Takahiro Hayashi ◽  
Akito Oshima ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Molecular Targeted Therapy ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mtor Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Hsp90 Inhibition ◽  
Pdx Models

Abstract The BRAFV600E mutation results in the constitutive activation of downstream mitogen activated protein kinase (MAPK) pathway that promotes tumor growth. Recently, molecular targeted therapy using BRAF/MEK inhibitor has been reported for BRAFV600E mutant high-grade glioma, but the therapeutic effect is limited by the emergence of drug resistance. Herein, we established paired BRAFV600E mutant glioblastoma (GBM) patient-derived xenograft (PDX) models, which were derived from tumors at prior to and recurrence after molecular targeted therapy. These PDX models were found to extensively recapitulate the histology, genetic abnormalities, and even the clinical course of the patients. Furthermore, BRAF/MEK inhibitor gradually caused resistance in cell lines derived from specimens that initially responded to molecular targeted therapy. In this study, genomic and epigenomic changes had little effect on the resistance mechanism. On the other hand, we found that hyperactivation of the MAPK pathway through c-Raf and the AKT/mTOR pathway primarily caused resistance to molecular targeted therapy in BRAFV600E mutant GBM. Through a high throughput drug screening, we find that HSP90 inhibitor with BRAF/MEK inhibitor coordinately deactivates MAPK pathway and AKT/mTOR pathway, and mediates potent toxicity in vitro and in vivo in refractory and acquired resistant models. These findings support that this therapeutic approach can overcome the limitation of current molecular targeted therapy in BRAFV600E mutant GBM.

scholarly journals Combination Therapy of Bcl-2/X L dual Inhibitor AZD0466 with Acalabrutinib to Overcome Therapeutic Resistance in Aggressive R/R Mantle Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1867-1867
Author(s):  
Yijing Li ◽  
Yang Liu ◽  
Yuxuan Che ◽  
Joseph McIntosh ◽  
Alexa A Jordan ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Research Funding ◽  
Single Agent ◽  
Dual Inhibitor ◽  
Car T ◽  
Mantle Cell

Abstract Introduction As a rare form of non-Hodgkin's lymphoma, mantle cell lymphoma (MCL) is an aggressive subtype. This is largely due to frequent relapses after therapies including paradigm shifting therapies BTK inhibitors (BTKi), such as ibrutinib and acalabrutinib, and Bcl-2 inhibitor (Bcl-2i) venetoclax after long-term treatment in the clinic. Dysregulation of Bcl-2 and Bcl-X L, contributes to therapeutic resistance in MCL. AZD0466 is a novel and highly potent Bcl-2/X L dual inhibitor with active moiety AZD4320. Our preliminary data showed AZD4320 is potent in inhibiting cell viability of MCL cells (IC 50 = 1.6-78 nM). In this study, we assessed the combination efficacy of AZD4320/AZD0466 and acalabrutinib on preclinical MCL models. Methods Cell viability assay was performed to assess the in vitro efficacy of AZD4320 and acalabrutinib alone or in combination in a panel of ibrutinib/venetoclax-sensitive and -resistant MCL cell lines. Cell apoptosis assay was also performed to determine if AZD4320 and acalabrutinib enhanced cell death by cell apoptosis in MCL cell lines. Protein expression profiles of a panel of pro- and anti-apoptotic proteins and other relevant proteins were detected by immunoblotting. Since AZD4320 is limited in preclinical model due to physicochemical properties and dose limiting cardiovascular toxicity, AZD0466, the drug-dendrimer conjugate of AZD4320, was used for in vivo experiment. In vivo efficacy of AZD0466 (34 mg/kg, weekly, iv) and acalabrutinib (20 mg/kg, BID, oral) alone or in combination was evaluated using a Mino-venetoclax-R (Mino-R) cell xenograft model and a PDX model derived from an ibrutinib-CAR-T dual-resistant MCL patient. Results AZD4320 in combo with acalabrutinib inhibited cell proliferation synergistically in both ibrutinib/venetoclax-sensitive and -resistant cell lines (combination index = 0.17-0.93). Compared to vehicle or either single agent, the combination enhanced cell apoptosis by increasing pro-apoptotic markers cleaved caspase 3 and cleaved PARP. In the xenograft mouse model derived from venetoclax-resistant Mino-R cells, co-treatment of AZD0466 and acalabrutinib decreased tumor size significantly compared to vehicle (n = 5, p < 0.0001) or either single agent (n = 5, p = 0.0118 and 0.0070, respectively). Furthermore, in the PDX mouse model derived from a patient relapsed subsequently from ibrutinib and CAR T therapy, the combination of AZD0466 and acalabrutinib inhibited tumor growth compared to vehicle or either single agent. Acalabrutinib or AZD0466 improved survival compared with vehicle by 14 days or 32 days, respectively. Compared to Acalabrutinib or AZD0466, the combination therapy extended survival by 25 days and 7 days, respectively. All mice tolerated the treatment dose without any weight loss compared to the vehicle or either single agent group. Conclusion Compared to AZD4320/AZD0466 and acalabrutinib, combination therapy demonstrated anti-MCL synergy both in vitro and in vivo. These findings suggest that targeting Bcl-2/X L and BTK is promising to overcome multiple acquired resistance phenotypes, including CD19 CAR T-cell therapy. Disclosures Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cidado: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Wang: DTRM Biopharma (Cayman) Limited: Consultancy; BeiGene: Consultancy, Honoraria, Research Funding; Physicians Education Resources (PER): Honoraria; Anticancer Association: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Epizyme: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; BGICS: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria; Celgene: Research Funding; Genentech: Consultancy; Loxo Oncology: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Molecular Templates: Research Funding; Lilly: Research Funding; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Oncternal: Consultancy, Research Funding; OMI: Honoraria; Newbridge Pharmaceuticals: Honoraria; Scripps: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Chinese Medical Association: Honoraria; Pharmacyclics: Consultancy, Research Funding; Juno: Consultancy, Research Funding; CStone: Consultancy; Bayer Healthcare: Consultancy; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Dava Oncology: Honoraria; Moffit Cancer Center: Honoraria; Mumbai Hematology Group: Honoraria.

scholarly journals mTOR Pathway and mTOR Inhibitors in Head and Neck Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Wei Gao ◽  
John Zeng Hong Li ◽  
Jimmy Yu Wai Chan ◽  
Wai Kuen Ho ◽  
Thian-Sze Wong
Keyword(s):  
Head And Neck Cancer ◽  
Targeted Therapy ◽  
Head And Neck ◽  
Neck Cancer ◽  
Xenograft Model ◽  
Mtor Inhibitors ◽  
Chemotherapeutic Agents ◽  
Therapeutic Effects

Head and neck cancer is the sixth most common type of Cancer worldwide. Since conventional treatment regimens are nonselective and are associated with systemic toxicities, intense investigations focus on molecular targeted therapy with high selectivity and low adverse effects. mTOR signaling pathway has been found to be activated in head and neck cancer, making it attractive for targeted therapy. In addition, expression levels of mTOR and downstream targets eIF4E, 4EBP1, S6K1, and S6 are potential diagnostic and prognostic biomarkers for head and neck cancer. mTOR inhibitors, such as rapamycin and its derivatives temsirolimus and everolimus, exhibit inhibitory effects on head and neck cancer in both in vitro cell line model and in vivo xenograft model. A large number of clinical trials have been initiated to evaluate the therapeutic effects of mTOR inhibitors on patients with head and neck cancer. mTOR inhibitor has potential as a single therapeutic agent or in combination with radiation, chemotherapeutic agents, or other targeted therapeutic agents to obtain synergistic repression on head and neck cancer.

scholarly journals Lenvatinib Inhibits Intrahepatic Cholangiocarcinoma Growth via Gadd45a-Mediated Cell Cycle Arrest

2021 ◽  
Author(s):  
Xia Yan ◽  
Dan Wang ◽  
Liping Zhuang ◽  
Peng Wang ◽  
Zhiqiang Meng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Primary Liver Cancer ◽  
Transcriptional Profiling ◽  
Cycle Arrest

Abstract Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, and its 5-year survival rate is less than 10%. Fibroblast growth factor receptor (FGFR) changes have been observed in 6%-50% of ICC patients, and patients with FGFR mutations have been shown to have more inert tumour biological activity than patients with wild-type FGFRs. Thus, as a pan-FGFR inhibitor, lenvatinib is supposed to play an anti-tumour role in ICC. However, no relevant experiments have been reported.Methods: Patients derived xenograft (PDX) model and cell line derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyse the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism.Reaults: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC.Conclusion: Our work firstly found that lenvatinib exerted excellent antitumor effect on ICC, mainly via inducing Gadd45a mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.

Secretory Clusterin as a Novel Molecular-targeted Therapy for Inhibiting Hepatocellular Carcinoma Growth

2020 ◽  
Vol 27 (20) ◽  
pp. 3290-3301
Author(s):  
Min Yao ◽  
Wenli Sai ◽  
Wenjie Zheng ◽  
Li Wang ◽  
Zhizhen Dong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Targeted Therapy ◽  
Molecular Targeted Therapy ◽  
English Language ◽  
Multiple Drug Resistance ◽  
Mrna Level ◽  
Bibliographic Databases ◽  
Multiple Drug

Background: Although secretory clusterin (sCLU) plays a crucial role in Hepatocellular Carcinoma (HCC) cells proliferation, Multiple Drug Resistance (MDR), metastasis and so on, its targeted effects and exact mechanism are still unknown. This review summarizes some new progress in sCLU as a molecular-targeted therapy in the treatment of HCC. Methods: A systematic review of the published English-language literature about sCLU and HCC has been performed using the PubMed and bibliographic databases. Some valuable studies on sCLU in HCC progression were searched for relevant articles with the keywords: HCC, diagnosis, MDR, as molecular-targeted in treatment, and so on. Results: The incidence of the positive rate of sCLU was significantly higher in HCC tissues as compared to the surrounding tissues at mRNA or protein level, gradually increasing with tumor-nodemetastasis staging (P<0.05). Also, the abnormal level of sCLU was related to poor differentiation degree, and considered as a useful marker for HCC diagnosis or independent prognosis for patients. Hepatic sCLU could be silenced at mRNA level by specific sCLU-shRNA or by OGX-011 to inhibit cancer cell proliferation with an increase in apoptosis, cell cycle arrest, reversal MDR, alteration of cell migration or invasion behaviors, and a decrease in GSK-3β or AKT phosphorylation in vitro, as well as significant suppression of the xenograft growth by down-regulating β-catenin, p-GSK3β, and cyclinD1 expression in vivo. Conclusion: Abnormal hepatic sCLU expression should not only be a new diagnostic biomarker but also a novel promising target for inhibiting HCC growth.

In Silico Study of Potential Cross-Kingdom Plant MicroRNA Based Regulation in Chronic Myeloid Leukemia

2020 ◽  
Vol 17 (2) ◽  
pp. 125-132
Author(s):  
Marjanu Hikmah Elias ◽  
Noraziah Nordin ◽  
Nazefah Abdul Hamid
Keyword(s):  
Targeted Therapy ◽  
In Silico ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Target Prediction ◽  
In Silico Analysis ◽  
Microrna Target ◽  
Good Target

Background: Chronic Myeloid Leukaemia (CML) is associated with the BCRABL1 gene, which plays a central role in the pathogenesis of CML. Thus, it is crucial to suppress the expression of BCR-ABL1 in the treatment of CML. MicroRNA is known to be a gene expression regulator and is thus a good candidate for molecularly targeted therapy for CML. Objective: This study aims to identify the microRNAs from edible plants targeting the 3’ Untranslated Region (3’UTR) of BCR-ABL1. Methods: In this in silico analysis, the sequence of 3’UTR of BCR-ABL1 was obtained from Ensembl Genome Browser. PsRNATarget Analysis Server and MicroRNA Target Prediction (miRTar) Server were used to identify miRNAs that have binding conformity with 3’UTR of BCR-ABL1. The MiRBase database was used to validate the species of plants expressing the miRNAs. The RNAfold web server and RNA COMPOSER were used for secondary and tertiary structure prediction, respectively. Results: In silico analyses revealed that cpa-miR8154, csi-miR3952, gma-miR4414-5p, mdm-miR482c, osa-miR1858a and osa-miR1858b show binding conformity with strong molecular interaction towards 3’UTR region of BCR-ABL1. However, only cpa-miR- 8154, osa-miR-1858a and osa-miR-1858b showed good target site accessibility. Conclusion: It is predicted that these microRNAs post-transcriptionally inhibit the BCRABL1 gene and thus could be a potential molecular targeted therapy for CML. However, further studies involving in vitro, in vivo and functional analyses need to be carried out to determine the ability of these miRNAs to form the basis for targeted therapy for CML.

scholarly journals mTOR inhibitors potentially reduce TGF-β2-induced fibrogenic changes in trabecular meshwork cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nozomi Igarashi ◽  
Megumi Honjo ◽  
Makoto Aihara
Keyword(s):  
Trabecular Meshwork ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Mtor Inhibitors ◽  
In Vivo Model ◽  
Type I ◽  
Fibrotic Response ◽  
Alpha Smooth Muscle Actin

AbstractWe examined the effects of mTOR inhibitors on the fibrotic response induced by transforming growth factor-beta2 (TGF-β2) in cultured human trabecular meshwork (hTM) cells. TGF-β2-induced expression of fibronectin, collagen type I, alpha 1 chain (COL1A1), and alpha-smooth muscle actin (αSMA) in hTM cells was examined in the presence or absence of mTOR inhibitors using quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The migration rates of hTM cells were examined in the presence of TGF-β2 with or without mTOR inhibitors. An in vitro study showed that the expression of fibronectin, COL1A1, and αSMA was upregulated by TGF-β2 treatment of hTM cells; such upregulation was significantly suppressed by mTOR inhibitors. The inhibitors significantly reduced the migration rate of TGF-β2-stimulated hTM cells. mTOR inhibitors may usefully reduce the fibrotic response of hTM cells and we may have to explore if it is also effective in in vivo model.

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

2019 ◽  
Vol 74 (11) ◽  
pp. 3211-3216 ◽  
Author(s):  
Stephan Göttig ◽  
Denia Frank ◽  
Eleonora Mungo ◽  
Anika Nolte ◽  
Michael Hogardt ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Selection Pressure ◽  
Galleria Mellonella ◽  
Phenotypic Characterization ◽  
Infection Model ◽  
Development Of Resistance ◽  
Time Kill

Abstract Objectives The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro. Methods Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination. Results The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival. Conclusions Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

scholarly journals STEM-20. RADIO-SENSITIZING GLIOBLASTOMA CANCER STEM CELLS BY INHIBITION OF FACT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi237-vi238
Author(s):  
Miranda Montgomery ◽  
Abigail Zalenski ◽  
Amanda Deighen ◽  
Sherry Mortach ◽  
Treg Grubb ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Cancer Stem Cells ◽  
Combination Therapy ◽  
High Rate ◽  
Primary Role ◽  
Cancer Cell Growth ◽  
Treatment Paradigm

Abstract Glioblastoma (GBM) has a particularly high rate of recurrence with a 5-year overall survival rate of approximately 5%. This is in part due to a sub-population of cancer stem cells (CSC), which are both radioresistant and chemotherapeutically resistant to conventional treatments. Here we investigated CBL0137, a small molecule form of curaxin, in combination with radiotherapy as a means to radiosensitize CSCs. CBL0137 sequesters FACT (facilitates chromatin transcription) complex to chromatin, which leads to activation of p53 and inhibition of NF-κB. This sequestering of FACT results in cytotoxicity especially within tumor cells and prevents FACT from performing its primary role as a histone chaperone, as well as inhibits its part in the DNA damage response pathway. We show that when combined with radiotherapy, CBL0137 administration limited the ability of CSCs to identify and repair damaged DNA. CSCs treated in vitro with CBL0137 and irradiation showed an increased inhibition of cancer cell growth and decreased viability compared to irradiation or drug alone. Combination therapy also showed more DNA damage in the CSCs than with either agent alone. Based on our in vitro evidence for the efficacy of combination therapy to target CSCs, we moved forward to test the treatment in vivo. Using a subcutaneous model, we show that the amount of CD133+ cells (a marker for GMB CSCs) was reduced in irradiation plus CBL0137 compared to either treatment alone. Survival studies demonstrated that irradiation plus CBL0137 compared to irradiation alone or CBL0137 alone increase lifespan. Here we show the ability of CBL0137, in combination with irradiation, to target patient GBM CSCs both in vitro and in vivo. This work establishes a new treatment paradigm for GBM that inclusively targets CSCs and may ultimately reduce tumor recurrence.

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